Adjei-Sowah, E. | Search bioRxiv

bioRxiv2024

Loss of Cochlin drives impairments in tendon structure and function

Aging tendons undergo disruptions in homeostasis, increased susceptibility to injury, and reduced capacity for healing. Exploring the mechanisms behind this disruption in homeostasis is essential for developing therapeutics aimed at maintaining tendon health through the lifespan. We have previously identified that the extracellular matrix protein, Cochlin, which is highly expressed in healthy flexor tendon, is consistently lost during both natural aging and upon depletion of Scleraxis-lineage cells in young animals, which recapitulates many aging-associated homeostatic disruptions. Therefore, we hypothesized that loss of Cochlin would disrupt tendon homeostasis, including alterations in collagen fibril organization, and impaired tendon mechanics. By 3-months of age, Cochlin-/- flexor tendons exhibited altered collagen structure, with these changes persisting through at least 9-months. In addition, Cochlin-/- tendons demonstrated significant declines in structural and material properties at 6-months, and structural properties at 9-months. While Cochlin-/- did not drastically change the overall tendon proteome, consistent decreases in proteins associated with RNA metabolism, extracellular matrix production and the cytoskeleton were observed in Cochlin-/-. Interestingly, homeostatic disruption via Cochlin-/- did not impair the tendon healing process. Taken together, these data define a critical role for Cochlin in maintaining tendon homeostasis and suggest retention or restoration of Cochlin as a potential therapeutic approach to retain tendon structure and function through the lifespan.

molecular biology↗

bioRxiv2023

Identification of Periostin as a critical niche for myofibroblast dynamics and fibrosis during tendon healing

Tendon injuries are a major clinical problem, with poor patient outcomes caused by abundant scar tissue deposition during healing. Myofibroblasts play a critical role in the initial restoration of structural integrity after injury. However, persistent myofibroblast activity drives the transition to fibrotic scar tissue formation. As such, disrupting myofibroblast persistence is a key therapeutic target. While myofibroblasts are typically defined by the presence of SMA+ stress fibers, SMA is expressed in other cell types including the vasculature. As such, modulation of myofibroblast dynamics via disruption of SMA expression is not a translationally tenable approach. Recent work has demonstrated that Periostin-lineage (PostnLin) cells are a precursor for cardiac fibrosis-associated myofibroblasts. In contrast to this, here we show that PostnLin cells contribute to a transient SMA+ myofibroblast population that is required for functional tendon healing, and that Periostin forms a supportive matrix niche that facilitates myofibroblast differentiation and persistence. Collectively, these data identify the Periostin matrix niche as a critical regulator of myofibroblast fate and persistence that could be targeted for therapeutic manipulation to facilitate regenerative tendon healing.

cell biology↗